Development of acquired multidrug resistance (MDR) is a major challenge in cancer chemotherapy. The possible mechanisms include high levels of mdr 1p-glycoprotein and the glutathione transferase (GST) and glutathione (GSH) repair mechanism. But neither mechanism explains the broad-spectrum nature of acquired MDR. Alteration of the apoptosis rheostat toward survival could explain the cross resistance among drugs that induce apoptosis through different action mechanisms. The clinical relevance of these mechanisms is not known as studies using Pgp or GSH inhibitors or antisense to Bcl-2 have not improved the efficacy of chemotherapy or have not been completed. We recently demonstrated that two fibroblast growth factors, i.e., acidic and basic FGF (aFGF and bFGF) that are expressed in solid tumors, induce a broad-spectrum resistance (up to 10-fold) to drugs with diverse structures and action mechanisms. Inhibitors of FGF binding to their receptors, including monoclonal antibodies and/or suramin, completely reverse the resistance induced by exogenous FGF. We further found that nontoxic and subtherapeutic doses of suramin enhance the efficacy of paclitaxel and doxorubicin in mice bearing human xenografts. Preliminary results of a phase I trial also suggest that suramin enhanced the efficacy of paclitaxel and carboplatin non-small cell lung cancer patients. Additional preliminary results indicate that short term (72 hour) and long-term (6 months) drug treatments enhanced the levels of intracellular and/or extracellular aFGF and bFGF, under in vitro and in vivo conditions, such that the post-treatment FGF levels were sufficient to induce drug resistance. The enhanced FGF levels were due to increased FGF production and secretion, and release of protein upon cell lysis. Drug treatment-induced resistance in cultured cells and xenografts was reversed by suramin. Finally, cDNA microarray results show that bFGF treatment altered the expression of GST, Bcl-2 family proteins, drug efflux proteins, and topoisomerases. These preliminary results, together with the literature data indicating that bFGF enhances GST and shifts the apoptosis rheostat toward survival, have led us to hypothesize that drug treatment induces increases in FGF levels, which in turn lead to acquired MDR, and that acquired MDR can be overcome by FGF inhibitors. The four Aims are as follows. (1) Establish that drug treatment enhances extracellular FGF levels. (2) Test the hypothesis that the FGF induction results in acquired MDR. (3) Test the hytpothesis that FGF is an upstream event that triggers several known mechanisms of acquired MDR. (4) Test the hypothesis that suramin can reverse acquired MDR under in vitro and in vivo conditions.